DE19648214A1 - Naphthyridine-3-carboxylic acid derivative preparation in high yield - Google Patents

Abstract

Preparation of a 1-aryl-1,4-dihydro-4-oxo-1,5-, 1,7- or 1,8-naphthyridine-3-carboxylic acid derivative of formula (I) comprises: (a) reacting a halogenated pyridine carboxylic acid chloride of formula (II) with an aminoacrylate ester of formula NR1R2-CH=CH-COOR' (III); (b) reacting the product of formula (IV) with an optionally substituted aniline of formula Ar-NH2 (V); (c) cyclising the obtained intermediate of formula (VI) by adding an acid scavenger to give (I; R = R'); and (d) optionally saponifying to give (I; R = H). One A = N and the other two = CH; R = H or 1-4C alkyl; Ar = optionally substituted phenyl; hal = F, Cl or Br; n = 1-3; provided that if A = N in the 8-position in (I) then n = 2 and the two hal groups are in the 6,7-positions, n being 2 and the two hal groups being in the appropriate positions relative to N in the corresponding compounds (II), (IV) and (VI); hal' = F or Cl; R' = 1-4C alkyl; R1,R2 = 1-6C alkyl (optionally with the chain interrupted by O, S or NH). Intermediates (VI) are new compounds.

Description

The present invention initially relates to an advantageous method for manufacturing position of the naphthyridinever characterized by formulas (Ia) to (Ic) below bonds and new intermediates, the key links for this ver are driving. Naphthyridine compounds of formulas (Ia) to (Ic) are valuable Intermediate products for the production of active ingredients, especially highly effective ones Bactericides (see, e.g., U.S. Patent 5,164,402, U.S. Patent 5,298,629 and EP-OS 413 455).

It is known to produce naphthyridine compounds of the formula (Ia) by reacting a halogenated nicotinic acid chloride with a malonic ester, then decarboxylating one of the two carboxylate groups, then converting the methylene group between the two carbonyl groups into an using an ortho-ester

transferred, the thus introduced alkoxy group with an optionally substi reacted aniline, thus obtaining a halogenated nicotinoylphenylaminoacrylate and from this by ring closure and optionally saponification to one Naphthyridine compound of the formula (Ia) comes (see, for example, DE-OS 35 14 076 and EP-OSs 132 845, 153 580, 160 758, 191 451, 302 372 and 449 445). The disadvantages of this method are the multi-stage and the low Total yield that is less than 40% of theory Th.

A process for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic)

in which
R represents hydrogen or C ₁ -C ₄ alkyl,
Ar for optionally substituted phenyl
Hal independently for fluorine, chlorine or bromine and
n stands for 1, 2 or 3, found,
which is characterized in that a halogenated acid chloride of the formulas (IIa) to (IIc)

in which
Hal and n have the meaning given in the formulas (Ia) to (c) and
Hal 'represents fluorine or chlorine,
with an aminoacrylic acid ester of the formula (III)

in the
R 'is C ₁ -C ₄ alkyl and
R ¹ and R ² independently of one another are C ₁ -C ₆ -alkyl, where the alkyl chain can in each case optionally be interrupted by O, S or NH,
thus receives intermediate compounds of the formulas (IVa) to (IVc)

in which
Hal and n are those given in the formulas (Ia) to (Ic),
Hal 'the given in formulas (IIa) to (IIc) and
R ', R ¹ and R ^{2 have} the meaning given for formula (III),
this with an optionally substituted aniline of the formula

H ₂ N-Ar (V),

in the
Ar has the meaning given in the formulas (Ia) to (Ic)
to form intermediate compounds of the formulas (VIa) to (VIc)

in which
Ar, n and Hal are those given in the formulas (Ia) to (Ic),
Hal 'the specified in the formulas (IIa) to (IIc) and
R 'have the meaning given for formula (III),
this cyclized by adding an acid scavenger to a compound of the formulas (Ia) to (Ic) with R = C ₁ -C ₄ -alkyl and, in the case of the preparation of compounds of the formulas (Ia) to (Ic) with R = H the compounds of the formula (Ia) to (Ic) are saponified with R = C ₁ -C ₄ -alkyl.

R 'and insofar as R is C ₁ -C ₄ -alkyl can each be straight-chain or branched and are, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. R preferably represents hydrogen, methyl or ethyl. R 'is preferably methyl or ethyl.

Means, unless Ar is substituted phenyl, suitable substituents are, for example, 1 to 4 same or different from the group of fluorine, chlorine, bromine, cyano, C ₁ - C ₆ alkyl and C ₁ -C ₆ -alkoxy present. Preferred substituents are 1 or 2 fluorine, chlorine and / or bromine atoms. Ar is preferably phenyl, 2,4-di fluorophenyl, 2-fluorophenyl or 4-fluorophenyl.

Hal preferably represents fluorine or chlorine. If there are two hal, stand preferably one for fluorine and the other for chlorine. If three hal before 1 to 2 are fluorine and the rest are chlorine. Next it is preferred that the carbon atom is in the meta position to the carbonyl group (this is the 6-position in formula (Ia) and the corresponding position in the other formulas) there is a fluorine substituent.

Hal 'preferably represents chlorine.

n is preferably 2.

R ¹ and R ² are preferably the same and each represent methyl or ethyl, in particular ethyl.

The reaction of compounds of the formulas (IIa) to (IIc) with a ver Binding of formula (III) can be carried out, for example, that the Compound of formula (III), a solvent and a base and a Compound of the formulas (IIa) to (IIc) metered. The reactants can be found in the Use principle in any relation to each other. From economic Er Weighing is the molar ratio of the compound of formulas (IIa) to (IIc) to Compound of formula (III) preferably 0.8 to 1.2: 1, especially 0.9 to 1.1: 1.

In principle, a wide variety of inorganic and organic bases can be used as bases. With bases which are sparingly soluble in the reaction mixture, e.g. B. anor ganic bases, it is advantageous to add a phase transfer catalyst. Organic bases, e.g. B. Amines. Particularly preferred are tertiary amines which, for. B. contain three identical or different C ₁ -C ₆ alkyl groups such as triethylamine. The amount of base should be at least the stoichiometrically required amount, preferably a small excess, e.g. B. up to 120 wt .-% of the stoichiometrically required amount.

Chlorinated hydrocarbons and aro are examples of solvents maten in question. Methylene chloride, dichloromethane, toluene and Xylene. The reaction temperature can range, for example, from -10 to + 80 ° C lie. In general, it is advantageous to reassemble after reassembling were left to stir at the reaction temperature for some time.

The overall process for the preparation of naphthyridine compounds of the formulas (Ic) to Ic) can be continued in the reactor in which the fully reacted Reaction mixture of the reaction of a compound of formulas (IIa) to (IIc) with a compound of formula (III) is present. Insulation of the manufactured It is not necessary to combine formulas (IVa) to (IVc).

If you look at the compound of formulas (IVa) to (IVc) anyway want to isolate e.g. B. to characterize them and / or for purposes other than for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic) can use z. B. proceed as follows: The fully reacted is transferred Reaction mixture with water, for example with 30 to 300 vol .-% (based on the reaction mixture), stirs well, then separates the aqueous from the organic phase and frees the organic phase from the solvent. One can so compounds of the formulas (IVa) to (IVc) in purities of over 95% obtained, which may be further cleaned using conventional methods can.

The reaction of a compound of formulas (IVa) to (IVc) with a ver Binding of formula (V) to a compound of formulas (VIa) to (VIc) can one z. B. perform so that a compound of the formulas (IVa) to (IVc), preferably in the form of the fully reacted resulting in their manufacture Reaction mixture, acidified and at temperatures below, for example 50 ° C, preferably below 40 ° C, optionally with cooling, a Ver bond of formula (V) metered. The compounds of the formulas (IVa) to (IVc) on the one hand and the formula (V) on the other hand, you can in principle in any ver Use relationships to each other. For economic reasons, the mole is ratio of the compound of the formulas (IVa) to (IVc) to the compound of the formula (V) preferably 0.8 to 1.2: 1, in particular 0.9. up to 1.1: 1.

In principle, a wide variety of inorganic and organic acids can be used for acidification. Preferred are C ₂ -C ₆ alkyl and C ₇ -C ₁₃ aryl carboxylic acids, especially acetic acid. The amount of acid can e.g. B. be chosen so that there is a slight excess with respect to the base used. The amount of acid can thus e.g. B. up to 125 equivalent%, based on the base used.

It is also advantageous here after the reactants have been combined stir for a while at the reaction temperature. After the completion of the Reaction it is advantageous to mix the reaction mixture e.g. B. 1 to 3 times with water to wash. The laundry can e.g. B. at temperatures from room temperature to 95 ° C. be performed.

The overall process for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic) can then, with the present one, essentially the one produced Compound of the formulas (VIa) to (VIc) and the solvent used containing solution to be continued. Insulation of the manufactured It is not necessary to combine formulas (VIa) to (VIc).

If you still the compound of the formulas (VIa) to (VIc) want to isolate e.g. B. to characterize them and / or for purposes other than for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic) can be used from the solution after washing with water remove the solvent. In this way, compounds of the formulas (VIa) to (VIc) of over 93% purity, which can be obtained with conventional methods can be further cleaned.

The cyclization of a compound of the formulas (VIa) to (VIc) to a compound of the formulas (Ia) to (Ic) with R = C ₁ -C ₄ -alkyl can, for. B. perform by metering in a compound of the formulas (VIa) to (VIc), preferably in the form of the solution obtained in its preparation, in the presence of a dipolar aprotic solvent to an acid scavenger. The dipolar aprotic solvent may e.g. B. dimethylformamide, dimethyl sulfoxide, tetramethylene sulfone or N-methylpyrrolidone. As acid scavengers come e.g. B. alkali metal salts such as alkali metal fluorides, carbonates, bicarbonates and hydrides in question. The following may be mentioned as individual examples: sodium fluoride, sodium hydride, sodium carbonate, sodium bicarbonate, potassium fluoride and potassium bicarbonate. It is advantageous to use the acid scavenger in an excess, for example in an excess of 10 to 50% by weight, based on the amount theoretically required. It is also advantageous to carry out the cyclization under as anhydrous conditions as possible.

If you have worked with an excess of acid scavengers, it is advantageous to neutralize this immediately after completion of the cyclization. For this you can, for example, add an aqueous acid until a pH z. B. in Range from 4 to 6 is present and temperatures in the range of z. B. 20 to 70 ° C adhere.

The isolation of the naphthyridine compounds of the formulas (Ia) to (Ic) with R = C ₁ -C ₄ alkyl can be obtained from the reaction mixture, for. B. make it so that it is mixed with water, the resulting mixture is stirred, the suspension formed is filtered off and the residue is washed successively with water and alcohol.

If naphthylridine compounds of the formulas (Ia) to (Ic) with R = H want to produce, an ester hydrolysis must be connected. This Saponification can be done e.g. B. with glacial acetic acid, water and mineral acid and the resulting acetic acid ester by distillation from the reaction remove mix.

One can thus naphthyridine compounds of the formulas (Ia) to (Ic) in purities of over 99%, often over 99.8%, and in yields (based on the amount used halogenated acid chloride of the formulas (IIa) to (IIc)) of more than 80% of theory Th. He hold.

The method according to the invention is not only due to these good results Visibly yield and purity advantageous, but also because it is particularly one fold, only requires two reaction vessels and without the isolation of Intermediate stages supplies high-purity products. With regard to the ge described prior art, this is extremely surprising.

The compounds of the formulas (VIa) to (VIc) are new. The present invention therefore also relates to compounds of the formulas

in which
R 'is C ₁ -C ₄ alkyl,
Hal independently of one another for fluorine, chlorine or bromine,
n for 1, 2 or 3,
Hal 'for fluorine or chlorine and
Ar represents optionally substituted phenyl.

The preferred meaning of the symbols R, Hal, n, Hal 'and Ar is as above specified.

Also above is a manufacturing process for the compounds of the formulas (VIa) to (VIc) and their use for the advantageous production of Naphthyridine compounds of the formulas (Ia) to (Ic) are described. The new Compounds of the formulas (VIa) to (VIc) are key compounds in the Process according to the invention for the preparation of naphthyridine compounds Formulas (Ia) to (Ic).

Examples example 1

Preparation of a compound of formula (IVa) with R '= ethyl, Hal in 5-position = fluorine, Hal in 6-position = chlorine, Hal' = chlorine and R ¹ = R ² = methyl.

47.2 g of ethyl β-dimethylaminoacrylic acid were added to 250 ml of methylene chloride and 35 g of triethylamine submitted. Over the course of 3 hours, 76 g 97% 2,6-dichloro-5-fluoronicotinic acid chloride was added dropwise. The temperature rose up to 55 ° C. At this temperature, stirring was continued for 1 hour and then cooled to room temperature. Now 250 g of water were added and ver stirs. The organic phase was then separated off and the methylene chloride was removed distilled. So 110 g of 97% product with a melting point of 94 ° C. receive.

H ¹ -NMR (DMSO): 0.95 ppm (t, CH ₂ CH ₃ ); 2.9 and 3.4 ppm (2 x s, N- CH ₃ ); 3.9 ppm (q, CH ₂ CH ₃ ); 7.95 ppm (br, S .; HC =); 8.04 ppm (d, Ar-H).

Example 2

Preparation of a compound of formula (VIa) with R '= ethyl, Hal in the 5-position = fluorine, Hal in the 6-position = chlorine, Hal' = chlorine, R ¹ = R ² = methyl and Ar = 2,4-difluorophenyl .

The procedure was initially as given in Example 1, but instead of Methylene chloride toluene used as a solvent. After cooling down Room temperature (= before washing with water) 22.5 g of glacial acetic acid were added and then 43 g of 2,4-difluoroaniline were metered in over the course of 30 minutes. After 1 hour stirring at 25 to 30 ° C, 250 ml of water were added and the Mixture heated to 80 ° C. The aqueous phase was then separated off and the organic phase washed again with 100 ml of water. Then was the toluene is removed from the organic phase in vacuo. It stayed behind 138.5 g of a 95% product with a melting point of 138 to 139 ° C.

H ¹ -NMR (DMSO): 1 ppm (t, 3H, CH ₂ CH ₃ ); 4 (q, 2H, CH ₂ CH ₃ ); 7.2, 7.5 and 7.9 ppm (per m, total 3H, Ar-H); 8.2 ppm (d, 1H nicotinoyl-H); 8.6 and 8.7 ppm (each d, 1H in HC = C, cis, trans), 11.6 and 12.6 ppm (each d, 1H in NH, cis, trans).

Example 3

Preparation of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naph tyridine-3-carboxylic acid ethyl ester (formula (Ia) with R = ethyl, Ar = 2,4-difluoro phenyl, Hal in 6-position = fluorine and Hal in 7-position = chlorine).

The first procedure was as in Example 2. The washed one obtained there toluene solution was heated to 60 ° C over 3 hours 250 ml of N-methylpyrrolidone and 28 g of anhydrous potassium carbonate dosed. At the same time, toluene was continuously distilled off in vacuo. After The end of the metering was stirred at 60 ° C. for 1 hour, then to 18 ° C. cooled down. 12 g of concentrated aqueous were added to this reaction mixture Hydrochloric acid and then 200 g of water and the resulting mixture Stirred for 30 minutes. A suspension was obtained which was filtered off and the The residue was washed successively with 120 g of Walser and 200 g of methanol. After drying, 105 g of 99.9% product melting at 215 ° C receive. This corresponds to an overall yield (based on the halogenated nicotinic acid chloride) of 84% of theory. Th.

H ¹ -NMR (DMSO): 1.3 ppm (t, 3H, CH ₂ C H ₃ ); 4.3 ppm (q, 2H, C H ₂ CH _3); 7.35, 7.65 and 7.9 ppm (m, total 3H, Ar-H); 8.55 ppm (d, 1H, nicotinoyl-H); 8.8 ppm (s, 1H, -CH =).

Example 4

85 g of the product from Example 3 became a mixture of 200 ml of glacial acetic acid and 50 ml of water. For this, 50 ml of conc. Added sulfuric acid, the mixture warmed to 60 ° C. To complete the saponification was continuously heated at 105 to 110 ° C for 4 h and the resulting Distilled off ethyl acetate. Then 250 ml of water were added up to 80 ° C. the precipitated product is filtered off at 22 ° C., washed with water and ge dries. Thus, 75 g of 99.9% product in the form of an inner salt hold.  

H ¹ -NMR (DMSO): 7.4, 7.65 and 7.9 ppm (per m, each 1H, Ar-H); 8.85 ppm (d, 1H Nictoninoyl-H); 9.05 ppm (s, 1H, -CH =).

Claims (9)

1. Process for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic)
in which
R represents hydrogen or C ₁ -C ₄ alkyl,
Ar for optionally substituted phenyl
Hal independently for fluorine, chlorine or bromine and
n stands for 1, 2 or 3,
characterized in that a halogenated acid chloride of the formulas (IIa) to (IIc)
in which
Hal and n have the meaning given in the formulas (Ia) to (c) and
Hal 'represents fluorine or chlorine,
with an aminoacrylic acid ester of the formula (III)
in the
represents C ₁ -C ₄ alkyl and
R ¹ and R ² independently of one another are C ₁ -C ₆ -alkyl, where the alkyl chain can in each case optionally be interrupted by O, S or NH,
an intermediate compound of the formulas (IVa) to (IVc) is obtained
in which
Hal and n are those given in the formulas (Ia) to (Ic),
Hal 'the given in formulas (IIa) to (IIc) and
R ', R ¹ and R ^{2 have} the meaning given for formula (III),
this with an optionally substituted aniline of the formula
H ₂ N-Ar (V),
in the
Ar has the meaning given in the formulas (Ia) to (Ic)
to form intermediate compounds of the formulas (VIa) to (VIc)
in which
Ar, n and Hal are those given in the formulas (Ia) to (Ic),
Hal 'the specified in the formulas (IIa) to (IIc) and
R 'have the meaning given for formula (III),
this cyclized by adding an acid scavenger to a compound of the formulas (Ia) to (Ic) with R = C ₁ -C ₄ -alkyl and, in the case of the preparation of compounds of the formulas (Ia) to (Ic) with R = H the Saponified compounds of formula (Ia) to (Ic) with R = C ₁ -C ₄ alkyl. 2. Connections of the formulas
in which
Ar, Hal, Hal 'and R' have the meaning given in claim 1. 3. The method according to claim 1, characterized in that in the formulas
R represents hydrogen, methyl or ethyl,
R 'represents methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl,
Ar is optionally substituted with 1 to 4 same or different substituents from the group fluorine, chlorine, bromine, cyano, C ₁ -C ₆ - alkyl and C ₁ -C ₆ alkoxy substituted phenyl,
R ¹ and R ^{2 are the} same and represent methyl or ethyl and
if two Hal are present, one for fluorine and the other for chlorine, and if three Hal are present, 1 to 2 for fluorine and the rest for chlorine and
Hal 'stands for chlorine. 4. Process according to claims 1 and 3, characterized in that the Compound of formula (III), a solvent and a base that Compounds of the formulas (IIa) to (IIc) in a molar ratio to (III) metered from 0.8 to 1.2: 1 and up to 120 wt .-% of the stochiometric the required amount of base. 5. The method according to claims 1, 3 and 4, characterized in that the connection of formulas (IVa) to (IVc) in the form of their Production of the fully reacted reaction mixture acidified and Temperatures below 50 ° C the compound of formula (V) in one Molar ratio (IVa) to (IVc): (V) from 0.8 to 1.2: 1 metered in. 6. The method according to claims 1 and 3 to 5, characterized in that to connect the formulas (VIa) to (VIc) in the form of their Preparation of the resulting solution in the presence of a dipolar, aprotic Solvent added to an acid scavenger, which is in excess is used and after the end of the cyclization the excess Neutralized acid scavenger by adding at 20 to 70 ° C aqueous acid sets a pH in the range 4 to 6. 7. The method according to claims 1 and 3 to 6, characterized in that one as acid scavenger alkali fluorides, carbonates, bicarbonates or  -hydrides in an excess of 10 to 50 wt .-%, based on theo uses the required amount. 8. A process for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic) with R = H according to claims 1 and 3 to 7, characterized in that a compound of the formulas (Ia) to (Ic) with R = C ₁ -C ₄ alkyl saponified with glacial acetic acid, water and mineral acid and the resulting acetic acid ester is removed from the reaction mixture by distillation. 9. Compounds of claim 2, characterized in that in the formulas (VIa) to (VIc)
R 'represents methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl,
Ar for phenyl optionally substituted with 1 to 4 identical or different substituents from the group fluorine, chlorine, bromine, cyano, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, if two Hal are present, one of them for Fluorine and the other is chlorine, and if there are three Hal 1 to 2 is fluorine and the rest is chlorine, and
Hal 'stands for chlorine.